Nu-benzyl-betachloropropionamide anticonvulsant article of manufacture



Patented May 11, 1954 N BENZYL BETACHLOROPROPIONAMIDE ANTICONVULSANT ARTICLE OF MANU- FACTURE Raymond W. Cunningham, Ben King Harned, and Mary 0. Clark, Pearl River, N. Y., assignors to American Cyanamid Company, New York, N. Y., a corporation of Maine No Drawing. Application July 22, 1952, Serial No. 300,348

6 Claims.

sions of various types but, unfortunately, most of these possess undesirable side reactions. Phenobarbital, for example, leads to dizziness, lethargy and incoordination in the patient. Trimethadione often causes dizziness, nervousness and visual disturbances. Paramethadione exhibits similar effects. Diphenylhydantoin often results in incoordination, gastric distress and other undesirable reactions in the patient. Certain anti-convulsants also have other toxic effects which lead to agranulocytosis and apiastic anemia. There is a need, therefore, for new anticonvulsant agents which are less toxic and have fewer side effects upon the patient.

We have found that the compound N-benzylbeta-chloropropionamide is a highly effective anti-convulsant agent. It is relatively more effective against epileptic seizures of the grand mal type than other types. It has remarkably low toxicity and does note tend to produce physiological disturbances such as those mentioned above and can be administered orally in dosage units of the size, type and kind to be described herein.

The compound N-benzyl-beta-chloropropionamide is a White crystalline solid which has a melting point of 94 C. and the following structural formula:

The compound and a process of preparing it is described in U. S. Patent No. 2,569,288, issued September 25, 1951, to Cassell and Kushner.

Extensive laboratory tests have established N- benzyl-beta-chloropropionamide as an eifective anti-convulsant of low toxicity. Clinical investigations have confirmed the laboratory results and the compound has been proven to be eiiective and reliable in treatment of both idiopathic and symptomatic epilepsy, note Hawkes, C. D.: N- Benzyl-beta-chloropropionamide (Hibicon), A. M, A. Archives of Neurology and Psychiatry 6'7; 815-820, June 1952.

Although the drug is only very slightly soluble in water, between about 0.005% and 0.01% by weight, it is readily absorbed by the body after oral administration. The efiective clinical dose for adults ranges from 0.5 to 1.5 grams taken 1 to 3 times daily. In children, the dosage ranges correspondingly lower according to the age and weight of the child. A preferred form of administration is a quantity of the drug Within the range of about 0.2 to 1.5 grams enclosed in a gelatin capsule. Capsules are preferred over other dosage unit forms because, while the compound is only slightly soluble in water, it has an unpleasant taste which is difiicult to mask by flavoring agents or other devices which are used in tablet manufacture. The capsule may be of either the hard shell or soft shell type and is generally of gelatin, although any water soluble capsulating material that will disintegrate after oral administration is suitable. Lubricants such as magnesium stearate and anti-caking agents to keep the drug in a readily dispersible form may be incorporated in the dosage unit.

When tablets are prepared, they may be made in various sizes containing from about 0.2 to 1.5 grams or more of the drug. These are generally compounded with binding agents, lubricants and other substances which are commonly used in tablet manufacture such as magnesium stearate, stearic acid, talc, corn starch, lactose or the like. If desired, these tablets may be coated with sugar or shellac preparations in accordance with the common practices in the tablet manufacturing art.

In illustration of the above, 500 parts by weight of N-benzyl-beta-chloropropionamide, parts of corn starch and 35 parts of gum acacia were mixed, moistened, granulated and dried. To this granulation was then added 1.74 parts by weight of magnesium stearate and the composition was pressed into scored tablets containing one-half gram each of N-benzyl-beta-chloropropionamide. These tablets may be administered orally to the patient at intervals of 4 to 8 hours, or whenever needed, in amounts depending upon the age and weight of the patient and the nature of the attack.

More preferably, the above described tablets are covered with a soft gelatin film on a capsulating machine to obtain capsules in which the effective ingredients are protected and the unpleasant taste of uncoated tablets is avoided.

A less preferred form of the invention is one of the above described tablets coated with sugar or other water-soluble coatings known to the art.

We claim:

1. An article of manufacture comprising a K quantity of from about 0.2 to 1.5 grams of N- benzyl-betach1oropropionamide and a pharmaceutical carrier in dosage unit form.

2. An article of manufacture comprising a quantity ranging from :-about 052 grams to 1.5 grams of N-benzyl-beta-chloropropionamide in a pharmaceutical capsule.

3. An article of manufacture comprising "a quantity ranging from about flzmtosl tggwmseof N-benzyl-beta-ch1oropropionamide in a ggelatin capsule.

4. A composition of matter comprising a quantity of from about 0.2 to l'fi grams ofiN-benzylbeta-chloropropionamide andan effectivetamount of a non-toxic pharmaceutical binding agent pressed together in a dosage unit form.

4 5. A composition or matter comprising a quantity of from about 0.2 to 1.5 grams of N-benzylbeta-chloropropionamide and an eifective amount of a non-toxic pharmaceutica1 binding agent 5 :presse'd together in a. tablet.

6. A composition of matter comprising a quantity of from about 0.2 to 1.5 grams of N-benzylbeta-chloropropionamide and an effective amount 10f 2a rnomtoxic pharmaceutical binding agent :presseditogetheraand coated to form tablets effective inccontrdll-ing epileptic seizures.

"Rferencesflited in the file of this patent ii-lowandizModem Drug Encyclopedia, fifth ed., *DnugFEaibLiIncorpu page 1203, New York, 1952. 

1. AN ARTICLE OF MANUFACTURE COMPRISING A QUANTITY OF FROM ABOUT 0.2 TO 1.5 GRAMS OF NBENZYL-BETA-CHLOROPROPIONAMIDE AND A PHARMACEUTICAL CARRIER IN DOSAGE UNIT FORM. 